Kallman syndrome is characterized by loss of
the sense of smell, anosmia and hypogonadotropic hypogonadism. The anosmia
results from absence or hypoplasia of the olfactory bulbs and tracts. The
hypogonadism is due to a deficiency of GnRH, probably the result of
failure of GnRH-synthesizing neurons to migrate from the olfactory
epithelium to the forebrain along the olfactory nerve pathway. Kallmann
syndrome occurs mainly in males and most often is inherited in an X-linked
recessive fashion; the gene responsible for this form has been identified,
KAL1. However, there are instances, such as failure to detect a
KAL1 mutation, that suggest an autosomal form of Kallmann syndrome.
Through segregation analysis of polymorphic markers and FISH
chromosomal analysis, Dodé et al identified two de novo deletions
of about 11 Mb at chromosome 8p11.2-p12 in two individuals affected by
different contiguous gene syndromes that included Kallmann syndrome. The
overlapping region of about 540 kb contained three genes, one of which,
FGFR1 (fibroblast growth factor receptor 1) was considered a strong
candidate for causing Kallmann syndrome because of its known interaction
with the KAL1 gene product, anosmin-1. Southern blot analysis of 43
individuals with familial or sporadic Kallmann syndrome failed to detect
additional deletions of FGFR1. However, sequencing of FGFR1
in 129 unrelated patients with Kallmann syndrome revealed heterozygous
mutations in four familial and eight sporadic cases. The mutations,
including nonsense, frameshift and splice-site mutations, predicted loss
of FGFR1 function.
These observations suggest that Kallmann syndrome can result from
haploinsufficiency or reduced dosage for FGFR1. The authors point
out that anosmin-1 binds to heparin sulfate proteoglycans which are
required for FGF ligands to bind to FGF receptors and that KAL1 and
FGFR1 are expressed in many of the same areas in the embryo
including the region of olfactory bulb development. They offer a possible
explanation for the higher prevalence of Kallmann syndrome in males even
in families with autosomal inheritance which is based on the assumption
that the local concentration of anosmin-1 is important to FGF signaling,
and the observation that KAL1 partially escapes X-inactivation.
Accordingly, females with two KAL1 alleles synthesize higher
amounts of anosmin-1 than do males with a single KAL1 allele. The
authors propose that this may be enough in some cases to maintain FGF
signaling above a critical threshold with regard to FGFR1 signaling
in the context of olfactory bulb and tract development.
Dodé C, et al. Loss-of-function Mutations in FGFR1 Cause
Autosomal Dominant Kallmann Syndrome. Nat Genet 2003;33:1-3.
First Editor’s Comment: FGFR1 joins a small group of genes for
which both gain and loss of function mutations are known and associated
with disease. It is not surprising that gain and loss of function
mutations lead to quite different clinical consequences. Gain of FGFR1
function causes craniosynostosis, especially Pfeiffer syndrome, while loss
of FGFR1 function results in Kallmann syndrome. Thus, these two syndromes
are technically allelic disorders. One wonders how common this phenomenon
actually is. Indeed, those of us with interest in FGFR3 have pondered if
some individuals with tall stature have loss of function mutations of this
gene in contrast to the gain of FGFR3 mutations that cause achondroplasia.
The paper also illustrates the importance of gene dosage. In some
instances, the precise dosage of a gene or its product does not seem to
matter so much. Examples include, metabolic disorders in which half the
normal amount of enzyme is more than enough to prevent disease and
mutations of structural proteins, where inclusion of variable amounts of
abnormal gene product can disrupt the formation of multimeric molecules
containing the products of both mutant and normal alleles. When mutations
involve regulation, such as mutations that affect signaling or formation
of transcription factor complexes, small differences may have large
effects on the outcome of the regulated events, especially if they involve
thresholds as proposed for FGFR1 signaling in this report.
William A. Horton, MD
Second Editor’s Comment: The authors have identified a second gene
involved in the pathogenesis of Kallmann syndrome. The large number of
subjects with Kallmann syndrome (N=116) in this study in whom mutations in
neither KAL1 or FGFR1 were found indicates that there are (many) more
genetic mutation which lead to this disorder. Search for involved genes
might be directed toward those that encode products known to be important
in neural cell migration and upon the intracellular proteins that are
phosphorylated and the downstream genes whose transcription is regulated
by FGFR1. It is interesting (curious?) that gain-of-function mutations of
FGFR1 are associated with the Pfeiffer syndrome of craniosynostosis, but
that inactivating mutations of this gene have not been linked to delayed
closure of cranial sutures.
Allen W. Root, MD
